Tumor suppressor genes are deleted or mutated with a high frequency in certain cancers including gliomas, melanomas, and carcinomas of the breast and lung. Loss of tumor suppressor gene function modifies the pathways of growth arrest and apoptosis following cancer treatment with radiation. The goal of this project is to validate whether adenoviral- mediated tumor suppressor gene transfer will overcome radiation resistance in tumor cells by and induce apoptosis. Tumor cell resistance remains a key limitation to the use of radiation in cancer treatment and novel gene therapy strategies deserve examination. Preliminary data support the efficacy of a certain gene, however additional translational studies and further product development must be performed before this gene can be taken to clinical trials in combination with radiotherapy. The specific aims will provide this information through examination of radiosensitization in preclinical in vitro and in vivo tumor models, delineation of the molecular mechanisms of radiosensitization, and initiation of the manufacture, quality control testing and assay development required for clinical development and commercialization of this tumor suppressor gene. Ultimately, the results of these efforts will allow assessment of this gene for its therapeutic benefit in the treatment of cancer in future clinical trials of this strategy. PROPOSED COMMERCIAL APPLICATION: According to the American Cancer Society there were an estimated 171,500 new cases of lung cancer in the USA in 1998. While lung cancer accounts for 14% of all cancers diagnosed, it is responsible for 28% of all cancer deaths. Despite advances in surgery, radiation therapy and chemotherapy, the overall 5 year survival rate in lung cancer is only 14%, mandating the need for novel forms of therapy. This unique application of gene therapy would expand anti-cancer gene therapy options for lung cancer by enhancing the effectiveness of radiotherapy.